Related Experiment Video
Updated: Jun 28, 2026
10:50
Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
Published on: April 24, 2021
Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally
1Department of Medicine, University of Wisconsin-Madison and Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin 53705, USA.
The Journal of Biological Chemistry
|November 18, 2008
Summary
Researchers discovered two new enzymes, ATase1 and ATase2, that acetylate BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1). This acetylation regulates BACE1 levels and amyloid beta-peptide generation, potentially impacting Alzheimer disease pathogenesis.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1) is crucial for amyloid beta-peptide generation in Alzheimer disease.
- Post-translational modifications regulate BACE1 function and stability.
- Nascent BACE1 undergoes acetylation in the endoplasmic reticulum (ER)/ER Golgi intermediate compartment (ER/ERGIC).
Purpose of the Study:
- Identify the enzymes responsible for BACE1 acetylation.
- Characterize the role of these enzymes in BACE1 regulation and amyloid beta-peptide generation.
- Investigate potential links to Alzheimer disease pathogenesis.
Main Methods:
- Protein interaction studies
- Enzyme activity assays (acetyl-CoA:lysine acetyltransferase)
- Cellular localization studies (ER/ERGIC)
- Analysis of BACE1 levels and amyloid beta-peptide generation
- Transcriptional regulation studies (ceramide treatment)
Main Results:
- Two novel ER/ERGIC-resident acetyltransferases, ATase1 and ATase2, were identified.
- ATase1 and ATase2 directly acetylate BACE1 at specific lysine residues.
- Both enzymes protect BACE1 from degradation and regulate its steady-state levels.
- ATase1 and ATase2 influence the rate of amyloid beta-peptide generation.
- Their expression is upregulated by ceramide treatment.
Conclusions:
- ATase1 and ATase2 are key regulators of BACE1 acetylation and function.
- These enzymes represent novel targets for understanding and potentially treating Alzheimer disease.
- Further research into ATase1, ATase2, and their regulation may reveal new therapeutic strategies for dementia.
Related Concept Videos
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
01:27Post-translational Translocation of Proteins to the RER
A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
01:28Assembly of the Lipid Bilayer in the ER
Biological membranes are more than just a barrier separating cell cytoplasm from the outside environment. They are highly dynamic and help maintain the integrity and physiological stability of the cells as well as membrane-bound organelles. Membranes also play vital roles in cell-to-cell and intracellular communication.
A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between...
A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between...
01:45ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
01:39Endoplasmic Reticulum
Endoplasmic ReticulumThe endoplasmic reticulum (ER) is an extensive network of membranous sacs and tubules in eukaryotic cells, continuous with the outer membrane of the nucleus. This structural continuity integrates nuclear and cytoplasmic processes and facilitates efficient intracellular transport. This allows mRNA to move directly from the nucleus to ribosomes for efficient protein synthesis. As a result, the ER serves as a central site for the synthesis, processing, and distribution of...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...